A major cause for the failure of cancer treatment is the resistance of cancer cells to radiotherapy and chemotherapy, which is believed to be due to abnormal expression and deregulation of oncogenes or anti-apoptotic factors, or most likely a combination of these. We have found that the inhibitor-of-apoptosis protein XIAP is upregulated by the overexpression of the MDM2 oncogene during cancer treatment, and it has been linked to cancer cell survival and resistance to apoptosis following radiation and chemotherapy. It is also already known that MDM2 in the nucleus and its phosphorylated form, which is regulated by PI3K/Akt survival signaling, can bind to and inhibit p53 activity. In addition, MDM2 exerts a p53-independent role in oncogenesis by mechanisms that are not completely understood. The goals of this project are to determine the p53- independent role of MDM2 in regulating XIAP translation in the development of drug resistance during cancer therapy and to evaluate the potential for targeting the MDM2-XIAP signaling pathway for use in the treatment of drug-resistant cancer patients. Preliminary studies have demonstrated that, in response to radiation, MDM2 is dephosphorylated and localized in the cytoplasm, where it can directly elevate XIAP protein levels. The proposed study seeks to further clarify the molecular mechanisms by which stress stimulation, including radiation and chemotherapy, modulates MDM2 and subsequently induces XIAP translation as well as to establish the linkage between MDM2's regulation of XIAP translation at the cellular level and the patient population's response to anticancer treatment. The specific aims of this project are: 1) To investigate the p53-independent role of MDM2 in regulating XIAP translation through an internal ribosome entry site (IRES)-dependent pathway and to characterize the interaction between the MDM2 protein and XIAP IRES; 2) To determine the link between MDM2-mediated XIAP translation and the response to cellular stress signaling triggered by anticancer treatment; 3) To target the MDM2 protein/XIAP mRNA interaction in order to inhibit XIAP translation, towards developing a novel approach to cancer treatment. Because the survival of various types of cancer patients whose neoplastic cells overexpress MDM2 remains very poor, our studies may help generate knowledge that can extend our current understanding of resistance to radiotherapy and chemotherapy and provide the basic framework for the rational design of new agents that can be used to treat these refractory cancer patients. More knowledge-based ways to treat patients with resistant and advancing cancers are greatly needed in the anticancer therapy arsenal. Our research should help pave a new path towards some of these much needed treatments for patients with refractory cancers.